FGF18 was identified as a member of the FGF family which was most closely related to FGF8 and FGF17. Activities associated with FGF18 include stimulation of mesenchymal lineage cells, in particular cardiac myocytes, osteoblasts and chondrocytes (U.S. Pat. No. 6,352,971). FGF18 binds and activates FGFR4 and the IIIc splice variant of FGFR3 and FGFR2.
Bone remodeling is the dynamic process by which tissue mass and skeletal architecture are maintained. The process is a balance between bone resorption and bone formation, with two cell types thought to be the major players. These cells are the osteoblasts and osteoclasts. Osteoblasts synthesize and deposit matrix to become new bone. The activities of osteoblasts and osteoclasts are regulated by many factors, systemic and local, including growth factors.
Cartilage is a type of dense connective tissue. It is composed of cells called chondrocytes, which are dispersed in a firm, gel-like ground substance, called the matrix. Cartilage is avascular (contains no blood vessels) and nutrients are diffused through the matrix. Cartilage is found in the joints, the rib cage, the ear, the nose, in the throat and between intervertebral disks. There are three main types of cartilage: hyaline, elastic and fibrocartilage. The main purpose of cartilage is to provide a framework upon which bone deposition could begin. Another important purpose of cartilage is to provide smooth surfaces and mechanical protection for the movement of articulating bones.
Replacement of damaged cartilage, in particular articular cartilage, caused either by injury or disease is a major challenge for physicians, and available treatments are considered unpredictable and effective for only a limited time. Virtually all currently available treatments for cartilage damage focus on pain relief, with little or no efficacy on regeneration of damaged tissues. Therefore, the majority of younger patients either do not seek treatment or are counseled to postpone treatment for as long as possible. When treatment is required, the standard procedure is total joint replacement or microfracture, a procedure that involves penetration of the subchondral bone to stimulate fibrocartilage deposition by chondrocytes.
For patients with osteoarthritis, non-surgical treatment consists of physical therapy, lifestyle modification (e.g. reducing activity), bracing, supportive devices, oral and injection drugs (e.g. non-steroidal anti-inflammatory drugs), and medical management. Surgical options are very specific to osteoarthritis severity and can provide a reduction in symptoms that are generally only short lived. Tibial or femoral osteotomics (cutting the bone to rebalance joint wear) may reduce symptoms, help to maintain an active lifestyle, and delay the need for total joint replacement. Total joint replacement can provide relief for the symptom of advanced osteoarthritis, but generally requires a change in a patient's lifestyle and/or activity level.
Therefore, it would be desirable to have a method for treating, preventing or ameliorating the symptoms of cartilage disorders that would permit regeneration of damaged tissue. In addition, it would be desirable that such method be as safe and effective as possible. Moreover, as cartilage disorders may be chronic diseases, it would be desirable that such method permits re-treatments of the patient.